Both laboratory-based and clinical data suggest that differences exist between male and female cocaine users. Unfortunately, the human data are sparse and results vary across laboratories and clinics. In contrast to female rats, female rhesus monkeys have menstrual cycles that are remarkably similar to human cycles in duration and hormonal variations. The goal of this proposal is to develop models for studying the reinforcing and discriminative effects of cocaine across the menstrual cycle in rhesus monkeys and to relate these changes to sex hormone status. We will track menstrual cycle status in females by collecting daily levels of estradiol and progesterone. The proposed research has 5 objectives: 1) determine the effects of single and multiple-doses of cocaine on luteinizing hormone (LH), cortisol (CORT) and cocaine plasma levels, heart rate and food intake across the menstrual cycle; 2) determine the reinforcing effects of intravenous cocaine, using a progressive-ratio self-administration procedure, across the menstrual cycle; 3) determine the effects of acute insulin-induced hypoglycemia (IIH), which decreases LH and increases CORT at most cycle phases, on the reinforcing and endocrine effects of cocaine across the menstrual cycle; and 4) determine if the cyclical pattern in the reinforcing efficacy of cocaine is similar to the cyclical pattern in the discriminative stimulus effects of cocaine across the menstrual cycle. Data will be collected at multiple phases of the menstrual cycle in females and at multiple time points in males. In the proposed studies, we will fully characterize the reinforcing, and discriminative effects of cocaine across the menstrual cycle in normally cycling adult female rhesus monkeys and intact males. Changes in the effects of cocaine across the menstrual cycle will be related to sex hormone status. The proposed studies will be the first to systematically evaluate these effects in non-human primates. The results will clarify an area of literature that is in disarray, in part because of the failure to adequately control for menstrual cycle in studies with human and non-human primates.